Chemical derivatives and methods for synthesizing and compounding chemical derivatives related to capsaicin palmitate and capsaicin prodrugs

ABSTRACT

Capsaicin compositions and methods for enhancing hydrophobicity of a molecule useful for pharmaceutical applications, including: (1) a prodrug using a linker such as a carbamate between capsaicin with other structures in order to optimize kinetic control of capsaicin cleavage; (2) a prodrug using a linker such as an unsaturated carboxylic ester between capsaicin with other structures in order to optimize kinetic control of capsaicin cleavage; (3) esters of long-chain fatty acids and capsaicin where hydroxyl groups provide handles for attachment of additional capsaicin molecules; and (4) the use of carboxylic acid diesters to increase overall hydrophobicity of two or more covalently-linked capsaicin molecules. Formulations of palmitated esters of capsaicin are also described, which are designed to enhance hydrophobicity of a molecule useful for pharmaceutical applications, for example to provide compounded mixtures designed to optimize analgesic efficacy.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 62/889,002 filed Aug. 19, 2019, the disclosure(s) ofwhich is incorporated herein by reference.

BACKGROUND Technical Field

The present invention relates to capsaicin compositions and methods forenhancing hydrophobicity of a molecule useful for pharmaceuticalapplications, for example to provide compounded mixtures designed tooptimize analgesic efficacy.

Background Art

Capsaicin is the pungent substance in hot chili peppers that causeschemical burning dermal irritation in any tissue of the body in which itcontacts. Paradoxically however, capsaicin can produce analgesia whenapplied as a topical medication. The present invention providesstructural modifications of capsaicin or the capsaicinoids (readcapsaicin) that modify the cleavage kinetics of the capsaicin prodrugmolecule in order to modify the time course of the capsaicin receptorbinding process.

A large body of literature demonstrates that capsaicin can produceexcellent analgesia. However due to burning, topical capsaicin productscurrently available for the treatment of pain are dose-limited due todermal irritation and burning, thereby resulting in poor-to-moderateefficacy and low patient compliance.

Capsaicinoids (including capsaicin), and their close analogs capsinoids,are comprised of a relatively polar vanillyl head group, a longhydrophobic tail, and an amide or ester linkage for capsaicinoids andcapsinoids respectively. While all three components (the head group, thehydrophobic tail, and the linkage) have been identified for theassociated biological and pharmacological activities, chemical synthesisof analogs of both families have been extensively carried out on thehead group and/or the hydrophobic tail. (For some of the recentexamples, see: Moriello, A. S. et al. J. Med. Chem., Just AcceptedManuscript, Publication Date (Web): 3 Sep. 2018; Serafini, M. et al. J.Med. Chem., 2018, 61, 4436-4455; Ramsaywack, S. et al. Canadian Journalof Chemistry, Manuscript ID: cjc-2018-0193.R1, date submitted: 2 Jul.2018; Aiello, F. et al. ACS Chem. Neurosci. 2016, 7, 737-748; Barbero,G. et al. J. Agric. Food Chem. 2010, 58, 3342-3349; Appendino, G. et al.J. Med. Chem. 2002, 45, 3739-3745.)

Starting from a general pharmacophore model of capsaicinoids andcapsinoids, efforts have also been devoted to the design and synthesisof antagonists and agonists targeting TRPV1 (transient receptorpotential vanilloid 1) for pain relief, resulting in small moleculesthat bear little resemblance to the natural ligands such as capsaicinand its natural derivative. (For selected examples, see: Mostinski, Y.et al. ACS Chem. Neurosci. 2017, 8, 1688-1696; Parsons, W. H. et al. J.Med. Chem. 2015, 58, 3859-3874; Blum, C. A. et al. J. Med. Chem. 2010,53, 3330-3348; Ognyanov, V. I. et al. J. Med. Chem. 2006, 49,3719-3742.)

Topical application of capsaicin typically causes intense burning overthe treatment area. Interestingly, capsiate, isolated from a uniquevariety of sweet chili pepper, and with an ester linkage in place of thesecondary amide linkage of capsaicin between the vanilloid head groupand the fatty acid tail, therefore a more hydrophobic molecule with oneless hydrogen bond to donate, causes essentially no such burningsensation. An ester prodrug formed between the capsaicin phenolichydroxyl on the vanilloid ring end and a fatty acid causes essentiallyno irritation when applied topically, presumably the increasedhydrophobicity and facilitated dermal uptake of the resulting moleculeplay a significant role (Singh, C. U. et al. U.S. Pat. No. 7,943,666).Depending on the applications and physiological environment, use ofester functionality, especially a saturated carboxylic acid ester, forthe protection of alcohol does sometimes present stability issues.Esters are also susceptible to enzymatic hydrolysis. The stability of anester depends on the structure of both the acid and the hydroxylpartners. A phenolic ester (ester formed between a carboxylic acid and aphenol) is more labile due to phenol being a better leaving groupcompared to an aliphatic alcohol (Blay, G. et al. Synthesis 1989,438-439). In addition to carboxylic esters, prodrugs of capsaicinoidshave also been generated between the phenolic hydroxyl group and anotherhydroxyl containing molecule using a carbonate ester linkage (Jamieson,G. C. et al. U.S. Pat. No. 7,632,519). Carbonate and ether linkages havealso been utilized for a transient phenolic alcohol protection usingphotolytically cleavable molecular partners (Katritzky, A. R. et al. J.Org. Chem. 2003, 68, 9100-9104).

The chemical stability of a carbamate is generally considered to besomewhere between an ester and an amide, and they can be substrates forboth esterases and amidases (for a recent review on prodrug approach indrug discovery, see: Rautio, J. et al. Nat. Rev. Drug Discov. 2018, 17,559-587). Examples of simple aliphatic amines conjugated to a capsaicinmolecule with a carbamate linkage, thereby functioning as a simpleprotecting group for the analgesics, exist in the literature (Boran, A.et al. Curr. Opin. Drug Discov. Devel. 2010, 13(3), 297-309).

Other work in related fields includes that described in U.S. Pat. Nos.7,632,519, 7,645,767, 7,771,760, 7,943,166, 7,943,666, 8,263,059,8,263,093, 8,273,390, 8,987,328, as well as U.S. Patent ApplicationPublication Nos. 2014/134261 and 2013/189354.

SUMMARY

The burning and painful sensations associated with capsaicin result fromits chemical interaction with sensory neurons. Capsaicin, as a member ofthe vanilloid family, binds to the vanilloid receptor subtype 1 (TRPV1).

Such undesirable sensations do not occur with compositions of thepresent disclosure. Unique, non-burning modifications of capsaicin aredisclosed through the formation of chemical bonds between capsaicin, alinking moiety and variable functional groups. Further, embodimentsherein show unique, non-burning modifications of capsaicin throughcompounding formulations with capsaicin palmitate and different classesof substances, as well as new drugs that can be made from homogenouscompounds made from capsaicin and other hydrophobic molecules inhydroscopic, hydrophobic media or in non-aqueous media, or aqueousmedia.

A variety of pharmaceuticals and foods have been palmitated. Palmiticacid is the most common cellular fatty acid and is a natural productfound in many compounds, including milk, plant congeners and waxes.Palmitated molecules are also ubiquitous as excipients, used in suchdiverse products as napalm and shampoos.

The use of palmitates includes retinyl palmitate. Palmitate is attachedto the alcohol form of vitamin A, retinol, to make vitamin A stable inmilk. Ascorbyl palmitate is also a food additive and increases thesolubility of vitamin C. Ethylhexyl palmitate is commonly used incosmetic formulations to provide a dry-slip feel similar to siliconederivatives. Paliperidone palmitate is a long-acting injectableformulation of paliperidone, a dopamine antagonist and 5-HT2A antagonistof the atypical antipsychotic class of medications. Testosteronepalmitate is a prodrug of testosterone associated with a long-lastingdepot effect and extended duration of action. While palmitated productswere designed essentially to enhance absorption, provide nutrients orreduce irritation, capsaicin palmitate is described here for use as acompounding pharmaceuticals in conjunction with substances in order toreduce topical irritation or to enhance the efficacy of capsaicinpalmitate. Examples of these compounding substances include cannabidiol,essential oils, waxes, jojoba oil, curcumin, hyaluronic acid, kinetinand nicotinamide.

The present pharmaceutical pro-drug molecules as described herein endowcapsaicin with heretofore undescribed linkages to the free alcohol ofcapsaicin by specific molecules, both conferring hydrophobicity to themolecule as well as steric hinderance to thereby producing andoptimizing o controlled release kinetics of the capsaicin molecule.These modifications would have the effect of easing or eliminating theburning sensation of capsaicin following topical application.

Esterification of the free hydroxyl group of capsaicin not onlyintroduces steric crowding around the phenolic head group, but alsoincreases the overall hydrophobicity of the molecule. Since theepidermis of the integument is also hydrophobic, the neutralizedfatty-acid CP molecule may be readily absorbed. Hydrolysis of an esterbond will occur with diffusion as the molecule encounters moisturelayers of the skin.

These molecules are drug conjugates made through linkages such ascarbamate, carboxyl esters and diesters. While carbamates have beenclaimed to produce analgesia, embodiments herein provide a mechanism bywhich a carbamate or pharmaceutical acceptable derivative of a carbamateis utilized as a connecting moiety to temporarily mask the free hydroxylgroup of the capsaicin molecule. More specifically, in embodiments ofthe invention, carbamates are used as linkers to form prodrugs that canincrease the time before the capsaicin molecule is chemically and/orenzymatically hydrolyzed and made free to bind to the TRPV-1 receptor.

Compounds described herein with sustained release properties would beclassified as pro-drug molecules. These molecules also modulate or evensynergize when linked with other drugs (menthol, morphine, and others).This would define these pro-drug configurations as “sustained release”molecules when devised as structures that are able to provide increasedkinetic stability from chemical or enzymatic hydrolysis or metabolicalteration of the capsaicin molecule.

In certain embodiments, amines with one extra functional group such as acarboxyl or a hydroxyl can be used as a handle for attachment of asecond molecule, either inert for additional hydrophobicity or amolecule with biological and pharmacological activity (such as a knowndrug) in order to pursue a polypharmaceutical therapy.

Additionally, the invention herein discloses the use of amine containingheterocycles or heteroaryls as capsaicin prodrug partners in order tomodulate the stability of the carbamate linkage. Together these can besummarized in a general formula as shown in FIG. 1.

It was shown that a carboxyl group directly connected to an unsaturatedhydrocarbon system is in general less reactive than the one connected toa saturated hydrocarbon system (for comparison of rate of hydrolyzingbenzoate vs acetate, see: Seidi, F. et al. Chem. Rev. 2018, 118,3965-4036). Here, the invention shows that when the free hydroxyl ofcapsaicin or a related analog is esterified to the carboxyl group of aα,β-unsaturated carboxylic diacid such as fumarate or maleate; theremaining carboxyl group can be esterified with a hydrophobic alcohol toincrease the overall hydrophobicity, or attached to another capsaicin toincrease the analgesic loading, or other free hydroxyl (OH) bearingmolecules. These scenarios are generalized in a formula as shown in FIG.2.

Esterification of capsaicin with simple hydrophobic carboxylic acids hasbeen shown to increase dermal uptake of the analgesics and reduceburning sensation, presumably due to the increased hydrophobicity of theoverall modalities. Here, in an embodiment, capsaicin esters can beprepared using very long chain (>C₂₀) fatty acids (VLCFAs). Some ofthese VLCFAs have been identified from the seed oils of natural plantorigin (Li, X. et. al. Nature Plants 2018). These natural fatty acidsusually contain an extra hydroxyl group which can be used as a handlefor the attachment of extra capsaicin molecule, or another molecule ofinterest for polypharmaceutical therapeutics purpose. These aregeneralized in a formula as shown in FIG. 3.

Building on the prodrug concept and increasing capsaicin loading, inanother embodiment, esters of capsaicin can be prepared with symmetricalsaturated carboxylic diacids. This is summarized in formulas as shown inFIGS. 4 and 4A.

The current invention discloses the design and synthesis of a series ofpro-drugs of capsaicin. These pro-drug molecules endow capsaicin withimproved uptake and delivery under different physiological conditionssuch as pain, and for various applications, such as topicaladministration formulations.

The current invention also discloses the design and synthesis of aseries of drugs that are designed as compounded drug formulations. Theseinclude different classes of chemicals, oils, drugs, waxes and naturalproducts. These formulations are combined as mixtures with capsaicinpalmitate without chemical bonds in order to make drug designs thatmitigate capsaicin burning at the epidermis such and in which none ofthe components are joined by covalent, ionic or hydrogen bonding.According to embodiments of the invention, capsaicin palmitate andcapsaicin palmitate with compounded drugs are formulated for topicalepidermal applications, oral (lingual, buccal), sterile injectable,inhalant, patch or plaster forms, or iontophoretic ways ofadministration.

Accordingly, aspects of the invention include Capsaicin/Capsaicinoiddrugs administered through topical vehicles, sterile injectablevehicles, patch or plaster vehicles, oral, inhalants or sublingual,iontophoretic or buccal formulations.

Aspects of the invention include Capsaicin/Capsaicinoid drugs that arecomprised of: (1) molecules that provide enhanced hydrophobicity ofcapsaicin due to covalent linkage with hydrocarbon moieties; and (2)molecules capable of cleavage to capsaicin or capsaicinoid compoundsfollowing dermal enzymatic or hydrolytic de-esterification.

Aspects of the invention further include compounds made withmodifications of capsaicin, including the following representativeclasses of compounds: (1) Capsaicin linked to different moieties by acarbamate linker (e.g., 3hydroxymethyl pyrrolidine, 4-aminobutanol,3-pyrrolidinyl acetic acid, 1-piperazine propanoic acid, prolinol,3-piperidinyl methanol, proline, nipecotic acid, morpholine,4piperidinone, 3,3-difluoropyrrolidine, 2-pyrrolidinone,pyrrole-2-carboxylate, 3-carboxyl H-pyrazole, 2-pyridone, pyridazinone)on the vanilloid ring-end of the capsaicin molecule; (2) Capsaicinlinked to different moieties by ester bond formation withα,β-unsaturated carboxylic acid (e.g., fumarate, maleate, acetylenedicarboxylate, terephthalate, 4,5-difluorophthalic acid) on thevanilloid ring-end of the capsaicin molecule; (3) Capsaicin linked todifferent moieties by ester bond formation with very long chaincarboxylic acids (>C20) on the vanilloid ring-end of the capsaicinmolecule; and (4) Capsaicin linked to different moieties by ester bondformation with symmetrical carboxylic diacids (e.g., 1,4-cyclohexanedicarboxylic acid, 1,3-cyclohexane dicarboxylic acid, cyclopropane1,1-dicarboxylic acid, succinic acid, adipic acid)) on the vanilloidring-end of the capsaicin molecule.

In another aspect, in an alternative to a carbamate linkage, the freephenolic hydroxyl group of capsaicin may be esterified with a carboxylicacid to generate a capsaicin prodrug with an ester linkage. Thecarboxylic acid is a α,β-unsaturated for the purpose of generating amore hydrolysis resistant ester bond (for example, alkenyl or benzoicacids). In addition, it is preferably a carboxylic di-acid with thepotential of using the second carboxyl group for increasing capsaicinloading, or to introduce a hydrophobic molecule to increase overallhydrophobicity of the prodrug, or a molecule with pharmaceuticalproperty to modulate the prodrug pharmacology. The ester formingcarboxylic acid can also be a long chain aliphatic acid. In this case,the overall number of carbon of the acid is over 20.

Aspects include formulations of drugs compounded with capsaicinpalmitate or derivatives or analogs of capsaicin palmitate aspharmaceutical mixtures.

Aspects also include methods for using and/or making any of thecompounds and/or compositions disclosed in any other Aspect. Specificmethods included are (1) methods of synthesis of hydrophobic drugscleaved to produce timedrelease of capsaicin or capsaicinoid moleculesfrom a linker molecule to carboxylic groups; and (2) methods offormulating compounded drugs with capsaicin palmitate or derivative oranalogs of capsaicin palmitate.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings illustrate certain aspects of embodiments ofthe present invention and should not be used to limit the invention.Together with the written description the drawings explain certainprinciples of the invention.

FIG. 1 is a schematic diagram showing a mechanism by which a linker isattached to nitrogenous cyclized or uncyclized hydrocarbons orheteroatom containing heterocycles to form a carbamate linkage with thefree phenolic hydroxyl group of capsaicin.

FIG. 2 is a schematic diagram showing a capsaicin joined to a carboxylgroup directly connected to an unsaturated hydrocarbon moiety.

FIG. 3 is a schematic diagram showing a capsaicin molecule esterified toa very long chain fatty acid (VLCFA) by way of its phenolic hydroxylgroup.

FIG. 4 is a schematic diagram showing a capsaicin molecule attached to asaturated hydrocarbon moiety with two carboxylic acid functional groupsby way of its phenolic hydroxyl group to form an ester bond.

FIG. 4A is a variant of the compound of FIG. 4, when the centralsaturated hydrocarbon moiety is a straight carbon chain.

BEST MODE FOR CARRYING OUT THE INVENTION

Reference will now be made in detail to various exemplary embodiments ofthe invention. It is to be understood that the following discussion ofexemplary embodiments is not intended as a limitation on the invention.Rather, the following discussion is provided to give the reader a moredetailed understanding of certain aspects and features of the invention.

As used herein, the term “prodrug” is meant to indicate a biologicallyinactive precursor compound which may undergo a chemical conversion inthe body to produce an active pharmacological agent.

The following drugs are designed to optimize the kinetics of the releaseof capsaicin. These compounds with capsaicin attached thus inhibit thebinding of capsaicin to its receptor (TRPV1), and release the capsaicinmolecule over time. The different carbamate moieties, molecularlinkages, and other non-carbamate, noncapsaicin linking or parentstructures are designed to release capsaicin, or to allow the cleavageof capsaicin from the structure, over different dissociation timeperiods, under different physiological environments, and for differentapplication and administration formats.

Carbamates

The starting structure for these compounds is capsaicin (R3 in thestructure below, and abbreviated Cpsn or CPS subsequently herein) and acarbamate functional group incorporated in a small molecular linkingmoiety (generalized as R2, R1), resulting in the protection of thehydroxyl group and as a capsaicin prodrug:

FIG. 1 shows a general format by which a linker is attached tonitrogenous cyclized or uncyclized hydrocarbons or a heteroatomcontaining heterocycles to form a carbamate linkage with the freephenolic hydroxyl group of capsaicin. In such a case, the other end ofthe linker is attached to a hydrophobic molecule or a molecule withbiological or physiological activities. In another embodiment, capsaicinis attached, by way of its free phenolic hydroxyl group, to ahydrocarbon or hetero hydrocarbon or heteroaryl moiety of variedstructural complexity through a carbamate bridge. These capsaicinanalogs are designed as simple prodrugs with the carbamate functionalityas the protective group with modulated stabilities (see formulas VII toIX, and X for example).

In one embodiment of the present invention, a method of synthesizing acapsaicin derivative chemical compound is provided using a process forthe preparation of molecules with a general chemical structure as shownin Formula I: Formula

-   -   wherein X=C or N;    -   R=H, or R=C(O)R′ where R′=1 to 20 hydrocarbons, straight,        branched, cyclized, saturated or unsaturated (examples include        but are not limited to: palmitate, oleate, abietic acetate,        etc.);    -   when X is a carbon (C): m=0 to 3, and n=0 to 2; in addition,        when m=1 or 3, the carbon X can be both racemic and chiral; and        when X is a nitrogen (N): m=2, and n=2.

Scheme 1 depicts an exemplary synthetic pathway to the prodrug ofFormula I, wherein EDC is an exemplary coupling reagent,1-Ethyl-3(3-dimethylaminopropyl)carbodiimide.

In another embodiment of the present invention, a method (Scheme 2) ofsynthesizing a capsaicin derivative chemical compound is provided usinga process for the preparation of molecules with a general chemicalstructure as shown in Formula II:

-   -   wherein X=C or N;    -   R=OH, or R═OR′ where R′=1 to 20 hydrocarbons, straight,        branched, cyclized, saturated or unsaturated, and/or R′ is        chosen from molecules with analgesic properties or other        pharmacological properties, such as capsaicin, cannabidiol etc.    -   when X is a carbon (C): m=0 to 3, and n=0; in addition, when m=1        or m=3, the carbon X can be both racemic and chiral; and    -   when X is a nitrogen (N): m=2, n=0 to 2; in addition, when X=N,        m=2, and n=0, then R=1 to 20 hydrocarbons, straight, branched,        cyclized, saturated or unsaturated (examples included but not        limited to: palmitate, oleate, abietic acetate, etc.).

See Scheme 2 depicts an exemplary synthetic pathway to the prodrug ofFormula II.

In another embodiment of the present invention, a method of synthesizinga capsaicin derivative chemical compound is provided using a process forthe preparation of molecules with a general chemical structure as shownin Formula III:

-   -   wherein X=C;    -   R=H, or R=C(O)R′ where R′=1 to 20 hydrocarbons, straight,        branched, cyclized, saturated or unsaturated (examples include        but are not limited to: palmitate, oleate, abietic acetate,        etc.); X is a methine (CH), and can be both racemic and chiral;        and m=1 to 2, n=1 to 2.

Compounds of Formula III can be prepared in a similar manner as inScheme 1.

In another embodiment of the present invention, a method of synthesizinga capsaicin derivative chemical compound is provided using a process forthe preparation of molecules with a general chemical structure as shownin Formula IV:

-   -   wherein X=C;    -   R=H, or R=C(O)R′ where R′=1 to 20 hydrocarbons, straight,        branched, cyclized, saturated or unsaturated (examples include        but are not limited to: palmitate, oleate, abietic acetate,        etc.); X is a methine (CH), can be both racemic and chiral; and        m=0 to 2.

Compounds of Formula IV can be prepared in a similar manner as in Scheme1.

In another embodiment of the present invention, a method of synthesizinga capsaicin derivative chemical compound is provided using a process forthe preparation of molecules with a general chemical structure as shownin Formula V:

-   -   wherein X=C;    -   R=H, R=1 to 20 hydrocarbons, straight, branched, cyclized,        saturated or unsaturated, and/or R is chosen from molecules with        analgesic properties or other pharmacological properties, such        as capsaicin, cannabidiol, etc.;    -   X is a methine (CH), can be both racemic and chiral; and m=1 to        2.

In addition, X is a methine (CH), can be both racemic and chiral; m=1 to2.

Compounds of Formula V can be prepared in a similar manner as in Scheme2.

In another embodiment of the present invention, a method of synthesizinga capsaicin derivative chemical compound is provided using a process forthe preparation of molecules with a general chemical structure as shownin Formula VI:

-   -   wherein X=C;    -   R=H, or R=1 to 20 hydrocarbons, straight, branched, cyclized,        saturated or unsaturated, and/or R is chosen from molecules with        analgesic properties or other pharmacological properties, such        as capsaicin, cannabidiol, etc.;    -   X is a methine (CH), can be both racemic and chiral; and m=1 to        2.

Compounds of Formula VI can be prepared in a similar manner as in Scheme2.

In another embodiment of the present invention, a method of synthesizinga capsaicin derivative chemical compound is provided using a process forthe preparation of molecules with a general chemical structure as shownin Formula VII:

-   -   wherein X=C or O, or X=sp3 or sp2 hybridized carbon (C);    -   m=1 to 2, n=1 to 2; Y=F or O (ketone); and    -   when m=2, n=1 or 2, X can be an oxygen (O), in which case Y can        be regarded as the oxygen lone pairs.

Scheme 3 depicts an exemplary synthetic pathway to the prodrug ofFormula VII,

related

In another embodiment of the present invention, a method of synthesizinga capsaicin derivative chemical compound is provided using a process forthe preparation of molecules with a general chemical structure as shownin Formula VIII:

m=1 to 3

Compounds of Formula VIII can be prepared in a similar manner as inScheme 3.

In another embodiment of the present invention, a method of synthesizinga capsaicin derivative chemical compound is provided using a process forthe preparation of molecules with a general chemical structure as shownin Formula IX:

-   -   wherein X=CH2 or CH (when m=1), m=1 to 3; and    -   when m=1, the bond between the two X atoms can be either a        single or a double bond.

Compounds of Formula IX can be prepared in a similar manner as in Scheme3.

In another embodiment of the present invention, a method of synthesizinga capsaicin derivative chemical compound is provided using a process forthe preparation of molecules with a general chemical structure as shownin Formula X:

In another embodiment of the present invention, a method of synthesizinga capsaicin derivative chemical compound is provided using a process forthe preparation of molecules with a general chemical structure as shownin Formula XI:

X, Y, and Z can be all carbons, or up to two nitrogen atoms, examplesinclude:

Compounds of Formula X can be prepared in a generally similar manner asin Scheme 3, using appropriately functionalized HNR1R2.

Unsaturated Carboxylic Acid Esters

In other embodiments, as shown in FIG. 2, a capsaicin molecule isattached to a α,β-unsaturated di-carboxylic acid by way of its phenolichydroxyl group to form an ester bond. The remaining carboxylic acid ofthe unsaturated moiety can be esterified to increase overallhydrophobicity of the molecule, or be attached to another molecule ofcapsaicin for increased loading, or be attached to a molecule withanalgesic property or other pharmacological property for modulating theoverall pharmacological properties of the molecule.

The starting structures for these compounds are capsaicin and acarboxylate functional group used as a linker between capsaicin and ahydrophobic molecule or a functionally active moiety attached using theremaining carboxylate of the unsaturated linking bridge (designated as Rbelow):

In embodiments, R may comprise: R=H, or R=1 to 20 hydrocarbons,straight, branched, cyclized, saturated or unsaturated, and/or R ischosen from molecules with analgesic properties or other pharmacologicalproperties, such as capsaicin, cannabidiol, etc.

In order to create more hydrophobicity and/or an “add-on” pharmacology,in embodiments, the di-carboxyl containing unsaturated molecular modulessuch as fumarate, maleate, and benzoate dicarboxylic acids can be used.A carboxylic acid is an organic compound containing carboxyl group(COOH) attached to an alkyl or aryl group. The general formula of acarboxylic acid is Ar/R—COOH where Ar/R represents the aryl or alkylgroup attached. In carboxylic acids, three of the four bonds of acarboxyl carbon atom are to two oxygen atoms:

A carboxyl group directly connected to unsaturated hydrocarbon system isless reactive than the one connected to a saturated hydrocarbon system(for comparison of rate of hydrolyzing benzoate vs. acetate, see: Seidi,F. et al. Chem. Rev. 2018, 118, 3965-4036). This scenario is summarizedin FIG. 2, wherein R=H, or R=1 to 20 hydrocarbons, straight, branched,cyclized, saturated or unsaturated, and/or R is chosen from moleculeswith analgesic properties or other pharmacological properties, such ascapsaicin, cannabidiol, etc.

Examples of unsaturated hydrocarbon moiety can be two carbon based, suchas:

Examples of the unsaturated hydrocarbon moiety can also be benzenedicarboxylic acid based, with up to 4 substitutions and up to 6 carbonson each substitution on the benzene ring. These side chain substitutionscan be straight, branched, or small rings. Substitutions can also beheavy atoms such as halogens (F, Cl, Br), oxygen (hydroxy, alkoxy) ornitrogen based; and various combinations among heavy atoms and withhydrocarbon side chains. Examples include but are not limited to:

A generalized synthesis of these α,β-unsaturated di-carboxylic acidesters is shown in Scheme 4, using fumarate di-ester as an example.

Esters Formed With Very Long Chain Fatty Acids (>C₂₀; VLCFAs)

In embodiments, shown in FIG. 3, a capsaicin molecule is esterified to avery long chain fatty acid (VLCFA) by way of its phenolic hydroxylgroup, wherein R=a hydrocarbon chain of over 20 carbon atoms in length.These types of fatty acids have been isolated from seed oils of naturalplant origin, such as castor oil from the seeds of the Ricinus communisplant, which can account for up to 50% of the seed oil by weight(Mubofu, E. B. Sustain Chem Process (2016) 4: 11.https://doi.org/10.1186/s40508-016-0055-8). In embodiments, the hydroxylgroups usually present in fatty acids can be used as handles forattachment of more capsaicin molecules for increased analgesic loading,or masked chemically (i.e., as small alkoxyls) to increasehydrophobicity of the molecules, or attachment of another molecule ofinterest.

Saturated Carboxylic Acid Diesters

FIG. 4 depicts a capsaicin molecule attached to a saturated hydrocarbonmoiety with two carboxylic acid functional groups by way of its phenolichydroxyl group to form an ester bond, wherein R=1 to 20 hydrocarbons,straight, branched, cyclized, saturated or unsaturated; or R=moleculeswith analgesic properties or other pharmacological properties, such ascapsaicin, cannabidiol, etc.

Alternatively, R=H (except when the central hydrocarbon moiety is astraight chain, in which case reference is made to FIG. 4A below). Thecentral hydrocarbon moiety can be straight, branched, or cyclized carbonchains containing up to 20 carbons. The remaining carboxylic acid of thediacid moiety may be esterified to increase overall hydrophobicity ofthe molecule, or may be attached to another capsaicin for increasedloading, or may be attached to a selected molecule with an analgesicproperty or other pharmacological property for potential modulation ofthe overall pharmacological profile.

When the central saturated hydrocarbon moiety is a straight carbonchain, the molecule can be depicted with a general structure as shown inFIG. 4A, wherein n=0 to 20 and R=H, when n is 0-1, or 4-20, or R=1 to 20hydrocarbons, straight, branched, cyclized, saturated or unsaturated,and/or R is chosen from molecules with analgesic property or otherpharmacological property such as capsaicin, cannabidiol, etc.

Representative central straight chain linkers include but are notlimited to oxalate (n=0), succinate (n=2), and adipic acetate (n=4).

The current invention discloses the design and synthesis of a series ofpro-drugs of capsaicin, which endow capsaicin with improved skin andcell membrane penetration, making possible a slower release of theanalgesics and thereby ease or eliminate the burning sensation as itpasses these biological barriers.

These pro-drug molecules are comprised of capsaicin attached to ahydrocarbon or hetero hydrocarbon or heteroaryl moiety through acarbamate bridge (FIG. 1), α,β-unsaturated carboxylic acid esters (FIG.2), very long chain fatty acid esters (FIG. 3), or symmetricaldicarboxylic acid esters (FIG. 4).

These structures can be expanded on by adding additional elements in asimilar format. Different forms of the compounds (e.g., stoichiometry,crystals, salts, formulations, purity characteristics, isomers,indications, dosing protocols, combinations, processes for preparing,etc.) may be considered.

Formulations

Pharmaceutical formulations are referred to here as compounded mixturesof pharmaceutically active ingredients. Usually a compounded formulationcontains selected inactive ingredients such as water, oil, surfactants,emulsifiers, stabilizers, chelators, preservatives, and pH-adjustingagents. The active ingredients may or may not be solubilized in thecarrier vehicle. Mixing pharmaceuticals typically combines two or morecomponents together by agitation, shear or mixers. The final product ofmixture usually contains uniform or homogeneous mixture of bothcomponents.

The following formulations are made from mixtures with palmitatedcapsaicin. The following drugs are designed to optimize the analgesicefficacy and to minimize dermal irritation with the use of capsaicinwith different classes of compounds. These compounds do not attach tocapsaicin but may mitigate the dermal irritation produced by capsaicin.

Cannibidiol (CBD) Essential Oils Waxes Hyaluronic acid JoJoba CurcuminKinetin Nicotinamide Palmitated Capsaicin Classes and RelatedCompounding Drugs

Formulations according to embodiments of the invention can include amixture or a structure such as a capsule, a pill, tablet, or anemulsion, prepared according to a specific procedure (called a“formula”). Formulations are important for creating medicines, sincethey are essential to ensuring that the active part of the drug isdelivered to the correct part of the body, in the right concentration,and at the right rate. Competently designed formulations for particularapplications are safer, more effective, and more economical than any oftheir components used singly.

Formulations of the invention include capsaicin bonded to any palmiticacid species with 1-20 carbon chains. Palmitic acid, or hexadecanoicacid, is one of the most common saturated fatty acids found in animals,plants, and microorganisms. As its name indicates, it is a majorcomponent of the oil from the fruit of oil palms (palm oil). Excesscarbohydrates in the body are converted to palmitic acid. Palmitic acidis the first fatty acid produced during fatty acid synthesis and is theprecursor to longer fatty acids. As a consequence, palmitic acid is amajor body component of animals.

Formulations of embodiments of the invention also include capsaicinbonded to any oleic acid species with 1-20 carbon chains. Oleic acid isan unsaturated fatty acid that is the most widely distributed andabundant fatty acid in nature. It is used commercially in thepreparation of oleates and lotions, and as a pharmaceutical solvent.

Additionally, embodiments of the invention include formulations withcapsaicin bonded to any linoleic acid species with 1-20 carbon chainssuch as formulations with capsaicin bonded to any ethylhexyl palmitate(octyl palmitate) or 2ethylhexyl species with 1-20 carbon chains.

Formulations of the present invention can include any one or more of thesubstances listed below compounded with capsaicin palmitate.

1. CANNIBIDIOL (CBD):(2-[(6R)-6-Isopropenyl-3-methyl-2-cyclohexen-1yl]-5-pentyl-1,3-benzenediol)and physically-modified derivatives or precursors of CBD. These arecompounds extracted from the marijuana plant.

Cannabidiol is an cannabinoid that is cyclohexene which is substitutedby a methyl group at position 1, a 2,6-dihydroxy-4-pentylphenyl group atposition 3, and a prop-1-en-2-yl group at position 4. It has a role as aplant metabolite. It is a member of resorcinols, an olefinic compoundand a phytocannabinoid.

Cannabidiol is a phytocannabinoid derived from Cannabis species, whichis devoid of psychoactive activity, with analgesic, anti-inflammatory,antineoplastic and chemopreventive activities. Upon administration,cannabidiol (CBD) exerts its anti-proliferative, anti-angiogenic andpro-apoptotic activity through various mechanisms, which likely do notinvolve signaling by cannabinoid receptor 1 (CB1), or vanilloid receptorTRPV1. CBD stimulates endoplasmic reticulum (ER) stress and inhibitsAKT/mTOR signaling, thereby activating autophagy and promotingapoptosis. In addition, CBD enhances the generation of reactive oxygenspecies (ROS), which further enhances apoptosis. This agent alsoupregulates the expression of intercellular adhesion molecule 1 (ICAM-1)and tissue inhibitor of matrix metalloproteinases-1 (TIMP1) anddecreases the expression of inhibitor of DNA binding 1 (ID-1). Thisinhibits cancer cell invasiveness and metastasis. CBD may also activatethe transient receptor potential vanilloid type 2 (TRPV2), which mayincrease the uptake of various cytotoxic agents in cancer cells. Theanalgesic effect of CBD is mediated through the binding of this agent toand activation of CB2 located on immune cells such as macrophages andsome nerve terminals.

Although the exact mechanism and magnitude of effects of THC and CBD arenot fully understood, CBD has been shown to have analgesic,anticonvulsant, muscle relaxant, anxiolytic, neuroprotective,anti-oxidant, and anti-psychotic activity. This wide variety of effectsis likely due to its complex pharmacological mechanisms. In addition tobinding to CB2 receptors of the endocannabinoid system, there isevidence that CBD activates 5-HT1A serotonergic and TRPV1-2 vanilloidreceptors, antagonizes alpha-1 adrenergic and μ-opioid receptors,inhibits synaptosomal uptake of noradrenaline, dopamine, serotonin andgaminobutyric acid and cellular uptake of anandamide, acts onmitochondria Ca2 stores, blocks low-voltage-activated (T-type) Ca2channels, stimulates activity of the inhibitory glycine-receptor, andinhibits activity of fatty amide hydrolase.

C₂₁H₃₀O₂ IUPAC 2-[(1R,6R)-3- methyl-6prop- 1-en-2-ylcyclo-hex-2en-1-yl]-5- pentyl- benzene1,3- diol

Synonyms include cannabidiol, 13956-29-1, (−)-Cannabidiol,(−)-transCannabidiol, CBD, Epidiolex, UNII-19GBJ60SN5,(−)-trans-2-p-Mentha-1,8-dien-3-yl-5pentylresorcinol, deltal(2)-trans-Cannabidiol, (−)-CBD, GWP42003-P, 19GBJ60SN5,

CHEMBL190461, CHEBI:69478, QHMBSVQNZZTUGM-ZWKOTPCHSA-N, 1,3-Benzenediol,2-(3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl)-5-pentyl-(1R-trans)-2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol,(1′R,2′R)-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydrobiphenyl-2,6-diol,Resorcinol, 2-p-mentha-1,8-dien-3-yl-5-pentyl-, (−)-(E)-Cannabidiol[USAN]. Related compounds include: Cannabidiolic acid (CBDa),Cannabigerol (CBG), Cannabichromene (CBC), Cannabielsoin (CBE),Cannabicyclol (CBL), Cannabicitran (CBT).

2. Essential and/or Essence Oils

Essential oils are compounds extracted from plants. The oils capture theplant's scent and flavor, also called its “essence.” Unique aromaticcompounds give each essential oil its characteristic essence. Essentialoils are claimed to have medicinal qualities, including aromatherapy,treating skin conditions, soothing muscle inflammation, to name a few.

Examples of essential oils that can be formulated with capsaicinpalmitate, include any one or more of the following (IUPAC namesprovided):

Arctium lappa, ext. extractives and their physically modifiedderivatives such as tinctures, concretes, absolutes, essential oils,oleoresins, terpenes, terpenefree fractions, distillates, residues,etc., obtained from Arctium lappa, Compositae.

Balsams, tolu, ext. extractives and their physically modifiedderivatives. This essential oil is comprised primarily of resins,essential oils, and usually cinnamic and benzoic acids, derived frommyroxylon balsamum, leguminosae.

Evernia furfuracea, ext. extractives and their physically modifiedderivatives such as tinctures, concretes, absolutes, essential oils,oleoresins, terpenes, terpene-free fractions, distillates, residues,etc., obtained from Evernia furfuracea, usnea.

Evernia prunastri, ext. extractives and their physically modifiedderivatives such as tinctures, concretes, absolutes, essential oils,oleoresins, terpenes, terpene-free fractions, distillates, residues,etc., obtained from Evernia prunastri, usneace.

Grapefruit, ext. Extractives and their physically modified derivativessuch as tinctures, concretes, absolutes, essential oils, oleoresins,terpenes, terpene-free fractions, distillates, residues, etc., obtainedfrom Citrus paradisi.

Lemon, ext. extractives and their physically modified derivatives suchas tinctures, concretes, absolutes, essential oils, oleoresins,terpenes, terpene-free fractions, distillates, residues, etc., obtainedfrom Citrus limonum, Rutaceae.

Orange, sweet, ext. extractives and their physically modifiedderivatives such as tinctures, concretes, and absolutes.

Star anise, Illicium verum, ext. extractives and their physicallymodified derivatives such as tinctures, concretes, absolutes, essentialoils, oleoresins, terpenes, terpene-free fractions, distillates,residues, etc., obtained from Illicium verum, Illiciaceae.

Eucalyptus maculata citriodora, ext. extractives and their physicallymodified derivatives such as tinctures, concretes, absolutes, essentialoils, oleoresins, terpenes, terpene-free fractions, distillates,residues, etc., obtained from Eucalyptus maculata citriodora, Myrtaceae.

Others: almond, argan, avocado, bergamot, black seed, borage,cannabidiol oil, cedar, chamomile, clary sage, coconut, emu, flaxseed,frankincense, grape seed, hemp seed, lavender, lemongrass, marjoram,neroli, palm, pumpkin, olive, patchouli, rose, rosehip, sandalwood,sunflower, vetiver, ylang-ylang, and vegetable oils.

Formulations of embodiments of the invention can include any one or morebotanical antimicrobial compositions described for example in U.S.Published Patent Application No. 2016/374352, which providesantimicrobial compositions comprising mixtures of botanical extracts,synthetic antimicrobial agents and essential oils which do not relysolely upon alcohol to produce their antimicrobial effects.

3. Waxes

Wax (wax esters). Waxes and waxy substances, jojoba, reaction productswith di-Bu phosphonate, fragrance products, wax blends and cosmetics canbe used in formulations of embodiments of the invention. Waxes aresometimes used for timed release depot mechanisms and controlled-releasedelivery systems having a stable-release pattern. Waxes for exampledescribed in U.S. Pat. No. 5,656,296 can be used in formulations of theinvention, such as natural waxes and/or synthetic waxes.

4. Hyaluronic Acid

Hyaluronic acid, ion (neg.); Hyaluronic acid sodium salt (a naturalhighviscosity mucopolysaccharide with alternating beta (1-3) glucuronideand beta (1-4) glucosaminidic bonds); N,N,N-tributyl-1-butanaminium;1-Butanaminium; N,N,Ntributyl-; hyaluronate (9C₁); Hyaluronic acidtetrabutylammonium salt; Tetrabutylammonium hyaluronate or Thiooctoylhyaluronic acid sodium salt; and related compounds, such as:

IUPAC Name: (2S,3S,4S,5R,6R)-6- [(2S,3R,4R,5S,6R)-3-acetamido-2-[(2S,3S,4R,5R,6R)-6- [(3R,4R,5S,6R)-3-acetamido- 2,5dihydroxy-6-(hydroxymethyl)oxan- 4-yl]oxy-2-carboxy- 4,5dihydroxyoxan-3-yl]oxy-5-hydroxy6-(hydroxymethyl)oxan-4- yl]oxy3,4,5-trihydroxyoxane-2-carboxylic acid

Synonyms for hyaluronic acid include: Healon, Hyaluronate Sodium,Hyalgan, Hyalurone sodium, Equron (veterinary), Synacid (veterinary),Hyaluronic acid, sodium salt, Hyaluronic acid sodium, Nrd101, CCRIS4127, Hyaluronate Sodium, SI-4402, SL-1010, Kopuron, Arthrease,Cystistat, Hyalart, Hyalein, Hyalovet, Hyladerm, Khionat, Monovisc,Nidelon, Orthovisc, Ostenil, Provisc, Sinovial, Supartz, Suvenyl,Hyasol, Hyladerm Khionat, Hyaluronsan HA-LQ, Bio Hyaluro 12, EUFLEXXAinjection, EUFLEXXA, Sodium hyaluronate HMW, UNII-YSE9PPT4TH, Synacid,Equron, Chlamyhyaluronic acid sodium salt, Suvenyl (TN), SL 1010,Hyalauronic Acid 99%, YSE9PPT4TH, DO7BSE, DOJ4NF, DOKZ3Z, AC1 MJ1T6, andGTPL4954.

5. Jojoba

Jojoba oil (C₁₆H₂₅NO₉) is a waxy liquid produced in the seed of theSimmondsia chinensis (Jojoba) plant, a shrub, which is native tosouthern Arizona, southern California, and northwestern Mexico.

Jojoba oil is used as an additive in many cosmetic products, especiallythose marketed from natural ingredients. In particular, such productscontaining jojoba are lotions and moisturizers, hair shampoos andconditioners. The pure oil itself may also be used on skin, hair, orcuticles. Jojoba oil can be hydrogenated, sulfonated, sulfurized.Extractives and their physically modified derivatives such as tinctures,concretes, absolutes, essential oils, oleoresins, terpenes, terpene-freefractions, distillates, residues, etc., obtained from Simmondsiachinensis N., Buxaceae can also be included in formulation embodimentsof the invention.

Synonyms for jojoba also include Butanedioic acid; sulfo-, 4-(2-jojobaoil amidoethyl) esters, disodium salts; Partially Hydrogenated JojobaOil; Simmondsin; Jojoba oil; jojoba-wax; bean-oil; UNII-O51H15R39K;O51H15R39K; 2-(Cyanomethylene)-3-hydroxy-4,5-dimethoxycyclohexylbeta-D-glucoside, 51771-529; Acetonitrile,((2S,3R,4S,6R)-6-(beta-D-glucopyranosyloxy)-2-hydroxy-3,4dimethoxycyclohexylidene)-,(2Z)-; Acetonitrile,(6-(beta-D-glucopyranosyloxy)-2hydroxy-3,4-dimethoxycyclohexylidene)-,(1Z,2-alpha,3-beta,4-beta,6-beta)-, Jojoba Meal Extract, and AC105NKM.Related compounds include Simmondsin:

7. Curcumin

1. Curcumin 2. Diferuloylmethane 3. Turmeric Yellow 4. Yellow, Turmeric(Search Terms) IUPAC Name (1E,6E)-1,7-bis(4- hydroxy3-methoxyphenyl)hepta1,6- diene-3,5-dione

Curcumin is a yellow-orange dye obtained from turmeric, the powderedroot of Curcuma longa. It is used in the preparation of Curcuma paperand the detection of boron. Curcumin appears to possess a spectrum ofpharmacological properties, due primarily to its inhibitory effects onmetabolic enzymes.

Curcumin is a phytopolylphenol pigment isolated from the plant Curcumalonga, commonly known as turmeric, with a variety of pharmacologicproperties. Curcumin blocks the formation of reactive-oxygen species,possesses antiinflammatory properties as a result of inhibition ofcyclooxygenases (COX) and other enzymes involved in inflammation; anddisrupts cell signal transduction by various mechanisms includinginhibition of protein kinase C. These effects may play a role in theagent's observed antineoplastic properties, which include inhibition oftumor cell proliferation and suppression of chemically inducedcarcinogenesis and tumor growth in animal models of cancer.

Curcumin is a natural component of the rhizome of turmeric (Curcumalonga) and one of the most powerful chemopreventive and anticanceragents. Its biological effects range from antioxidant, anti-inflammatoryto inhibition of angiogenesis and is also shown to possess specificantitumoral activity. The molecular mechanism of its varied cellulareffects has been studied in some details and it has been shown to havemultiple targets and interacting macromolecules within the cell.Curcumin has been shown to possess anti-angiogenic properties and theangioinhibitory effects of curcumin manifest due to down regulation ofproangiogenic genes such as VEGF and angiopoitin and a decrease inmigration and invasion of endothelial cells. One of the importantfactors implicated in chemoresistance and induced chemosensitivity isNFkB and curcumin has been shown to down regulate NFkB and inhibit IKBkinase thereby suppressing proliferation and inducing apoptosis. Celllines that are resistant to certain apoptotic inducers and radiationbecome susceptible to apoptosis when treated in conjunction withcurcumin. Besides this it can also act as a chemopreventive agent incancers of colon, stomach and skin by suppressing colonic aberrant cryptfoci formation and DNA adduct formation.

Curcumin acts as a scavenger of oxygen species, such as hydroxylradical, superoxide anion, and singlet oxygen and inhibit lipidperoxidation as well as peroxide-induced DNA damage. Curcumin mediatespotent anti-inflammatory agent and anti-carcinogenic actions viamodulating various signaling molecules. It suppresses a number of keyelements in cellular signal transduction pathways pertinent to growth,differentiation, and malignant transformation; it was demonstrated invitro that curcumin inhibits protein kinases, c-Jun/AP-1 activation,prostaglandin biosynthesis, and the activity and expression of theenzyme cyclooxygenase (COX)-2.

Synonyms include curcumin, 458-37-7, Diferuloylmethane, Natural yellow3, Turmeric yellow, Curcuma, Turmeric, Kacha haldi, Gelbwurz, Indiansaffron, Curcumin I, Souchet, Haidr, Halad, Haldar, Halud, Merita earth,Terra Merita, Yellow Ginger, Yellow Root, Safran d'Inde, Yo-Kin, Curcumaoil, Golden seal, Orange Root, Oils, Curcuma, C.I. Natural Yellow 3,Curcumine, Hydrastis, Indian turmeric, Yellow puccoon,Diferaloylmethane, Turmeric extract, Kurkumin [Czech],(1E,6E)-1,7-Bis(4hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione,Tumeric yellow, Turmeric oil, Oil of turmeric, Cl Natural Yellow 3, andTurmeric oleoresin.

8. KINETIN

IUPAC Name N-(furan-2-ylmethyl)-7H-purin- 6amine

Kinetin, also known as 3H-Purin-6-amine, N-(2-furanylmethyl)-,6-[(Furan2-ylmethyl)amino]-9H-purine, and2-{[(9H-Purin-6-yl)amino]methyl}furan;6-{[(Fur-2yl)methyl]amino}-9H-purine, is a type of cytokinin, aphytohormone, a plant growth regulator, a class of plant hormone thatpromotes cell division.

Kinetin is a furanyl adenine found in planta and fungi. It has plantgrowth regulation effects. Kinetin is a type of cytokinin, a class ofplant hormone that promotes cell division. Kinetin was originallyisolated by Miller and Skoog et al. as a compound from autoclavedherring sperm DNA that had cell division-promoting activity. It wasgiven the name kinetin because of its ability to induce cell division,provided that auxin was present in the medium.

Kinetin can react with UDP-D-glucose to produce kinetin-7-N-glucoside orkinetin-9-N-glucoside, with UDP as a byproduct. The reaction iscatalyzed by UDP glycosyltransferase. Kinetin is a hormone derived fromplants.

Kinetin is a member of the class of 6-aminopurines that is adeninecarrying a (furan-2-ylmethyl) substituent at the exocyclic amino group.It is a member of furans and a member of 6-aminopurines.

Synonyms include Kinetin HCL; kinetin; 525-79-1; 6-Furfurylaminopurine;6-Furfuryladenine; 6-(Furfurylamino)purine; N6-Furfuryladenine;N-Furfuryladenine; Cytokinin; N-(furan-2-ylmethyl)-9H-purin-6-amine;Cytex; N6-(Furfurylamino)purine; Kinetin (plant hormone);N-(furan-2-ylmethyl)-7H-purin-6-amine; Furfuryl(purin-6yl)amine;Adenine; N-furfuryl-1H-PURIN-6-AMINE; N-(2-FURANYLMETHYL)-; Kinetin(VAN); n(6)-furfuryladenine; Caswell No. 272D; 2-Furanmethanamine;N-1H-purin-6-yl-; N(sup 6)-Furfuryladenine; 9H-Purin-6-amine,N-(2-furanylmethyl)-; NSC 23119; UNIIP39Y9652YJ;N-(2-Furanylmethyl)-1H-purin-6-amine;N-(furan-2-ylmethyl)-1H-purin-6amine; N(sup 6)-(Furfurylamino)purine;HSDB 7429; EINECS 208-382-2; and EPA Pesticide Chemical Code 116801.

Compositions and compounds described in Chiu PC, Chan CC, Lin HM, ChiuHC: The clinical anti-aging effects of topical kinetin and niacinamidein Asians: a randomized, double-blind, placebo-controlled, split-facecomparative trial. J Cosmet Dermatol. 2007 December; 6(4):243-9 can alsobe used in formulation embodiments of the invention, as well ascompounds and compositions described in any one or more of U.S. Pat.Nos. 8,729,025; 8,404,660; and 8,222,260; and/or U.S. Patent ApplicationPublication Nos. 2009/143279; 2008/139664.

9. NICOTINAMIDE C₆H₆N₂O IUPAC pyridine-3-carboxamide

Nicotinamide, also known as niacinamide, is a form of vitamin B3 foundin food and used as a dietary supplement and medication. As asupplement, it is used by mouth to prevent and treat pellagra (niacindeficiency). While nicotinic acid (niacin) may be used for this purpose,nicotinamide has the benefit of not causing skin flushing. As a cream,it is used to treat acne.

Niacinamide is the active form of vitamin B3 and a component of thecoenzyme nicotinamide adenine dinucleotide (NAD). Niacinamide acts as achemo- and radio-sensitizing agent by enhancing tumor blood flow,thereby reducing tumor hypoxia. This agent also inhibitspoly(ADP-ribose) polymerases, enzymes involved in the rejoining of DNAstrand breaks induced by radiation or chemotherapy.

Niacinamide or vitamin B3 is an important compound functioning as acomponent of the coenzyme NAD. Its primary significance is in theprevention and/or cure of blacktongue and pellagra. Most animals cannotmanufacture this compound in amounts sufficient to prevent nutritionaldeficiency and it therefore must be supplemented through dietary intake.Niacinamide is used to increase the effect of radiation therapy on tumorcells. Niacin (nicotinic acid) and niacinamide, while both labeled asvitamin B3 also have different applications. Niacinamide is useful inarthritis and early-onset type I diabetes while niacin is an effectivereducer of high cholesterol levels. Related compounds includeIsonicotinamide, Nicotinamide riboside, and the following:

Synonyms include nicotinamide, niacinamide, 98-92-0,3-Pyridinecarboxamide, Nicotinic acid amide, pyridine-3-carboxamide,vitamin PP, Papulex, Aminicotin, Amixicotyn, Nicobion, Nicotylamide,Nikotinamid, Savacotyl, Benicot, Dipegyl, Endobion, Hansamid, Pelmine,Nicotinic amide, Delonin amide, Pelonin amide, Vi-Nicotyl, Austrovit PP,Inovitan PP, Vitamin B, Nicosylamide, Nicotilamide, Nicotililamido,Amnicotin, Niacevit, Nicamina, Nicamindon, Nicofort, Nicomidol,Nicotamide, Nicovitina, Nicovitol, Nicozymin, Niocinamide, Niozymin,Niamide, Nicasir, Nicogen, Nicota, Nicotol, Nicovit, Niko-tamin, and3-Carbamoylpyridine, Nicotine a. Any one or more of these can beincluded in the formulations according to embodiments of the invention,including and composition or compound described in U.S. Pat. No.8,288,434.

Particular Embodiments

Embodiments of this disclosure are meant to include the followingchemicals directed in use as described and including palmitic moleculesand the capsaicinoids, capsaicin analogs and derivatives outlined below:

A carbamate is an organic compound derived from carbamic acid (NH2COOH).A carbamate group, carbamate ester (e.g., ethyl carbamate), and carbamicacids are functional groups that are inter-related structurally.Carbamate esters are also called urethanes.

A carboxylate is the conjugate base of a carboxylic acid. Carboxylateesters have the general formula RCOOR′. R and R′ are organic groups;R′≠H. A carboxylic acid is an organic compound that contains a carboxylgroup. The general formula of a carboxylic acid is R—COOH, with Rreferring to the rest of the molecule.

Capsaicin is used as an analgesic in topical ointments, salves, creamsand dermal patches to relieve pain, typically in concentrations between0.025% and 0.1%. Capsaicin achieves its pain-relieving effect byreversibly depleting sensory nerve endings of Substance P, anundecapeptide released from sensory nerves and by reducing the densityof epidermal nerve fibers, in a reversible manner. Related compoundsinclude the following:

RELATED COMPOUNDS N-((4-(2-Aminoethoxy)- 3methoxyphenyl)methyl)-9octadecenamide

Sodium nonivamide acetate; Acetic acid, (2-methoxy-4-(((1oxononyl)amino)methyl)phenoxy) monosodium salt

Capsaicinoids:

Capsaicinoids and their close analogs capsinoids, are comprised of arelatively polar vanillyl head group, a long hydrophobic chain, and anamide or ester linkage for capsaicinoids and capsinoids respectively.While all three components have been identified as critical for theassociated biological and pharmacological activities, chemical synthesisof analogs of both families have been extensively carried out on thehead group and/or the hydrophobic chain (for some of the recentexamples, see: Moriello, A. S. et al. J. Med. Chem., Just AcceptedManuscript, Publication Date (Web): 3 Sep. 2018; Serafini, M. et al. J.Med. Chem., 2018, 61, 4436-4455; Ramsaywack, S. et al. Canadian Journalof Chemistry, Manuscript ID: cjc-2018-0193.R1, date submitted: 2 Jul.2018; Aiello, F. et al. ACS Chem. Neurosci. 2016, 7, 737-748; Barbero,G. et al. J. Agric. Food Chem. 2010, 58, 3342-3349; Appendino, G. et al.J. Med. Chem. 2002, 45, 3739-3745). Based on a general pharmacophoremodel of capsaicinoids and capsinoids, large efforts have also beendevoted to the design and synthesis of antagonists and agoniststargeting TRPV-1 for pain relief, resulting in small molecules that bearlittle resemblance to the natural ligands such as capsaicin and capsicin(for selected examples, please see: Mostinski, Y. et al. ACS Chem.Neurosci. 2017, 8, 1688-1696; Parsons, W. H. et al. J. Med. Chem. 2015,58, 3859-3874; Blum, C. A. et al. J. Med. Chem. 2010, 53, 3330-3348;Ognyanov, V. I. et al. J. Med. Chem. 2006, 49, 3719-3742).

Topical application of capsaicinoids causes intense burning over thetreatment area. Capsaicinoids may include the following:

Capsaicinoids Capsaicin

Dihydrocapsaicin

Nordihydrocapsaicin

Homocapsaicin

Homodihydrocapsaicin

Nonivamide (synthetic)

Includes capsaicinol, capsaicin diacetate, capsaicin dipalmate andcapsazepine.

Palmitates:

Palmitates are the salts and esters of palmitic acid.

Palmitic acid is the first cellular fatty acid produced during fattyacid synthesis and is the precursor to longer fatty acids.

This embodiment includes di- and tri-palmitic acid, Glycerin di- andtripalmiate, palmitin and their palmitic esters.

Capsiate, with an ester linkage between the vanilloid head group and thefatty acid tail, and an overall more hydrophobic molecule, does notcause such burning sensation. An ester prodrug formed between thecapsaicin phenolic hydroxyl and a long chain fatty acid causesessentially no irritation when applied topically, presumably theincreased hydrophobicity and facilitated dermal uptake of the resultingmolecule play a significant role (Singh, C. U. et al. U.S. Pat. No.7,943,666). Use of ester for the protection of alcohol has hydrolytic orinstability liability since esters are prone to enzymatic hydrolysis.The stability of an ester depends on the structure of both the acid andthe hydroxyl partners. A phenolic ester (ester formed between acarboxylic acid and a phenol) is particularly labile due to phenol beinga better leaving group compared to an aliphatic alcohol (Blay, G. et al.Synthesis 1989, 438-439). Besides esters, prodrugs of capsaicinoids havealso been generated between the phenolic hydroxyl group and anothermolecule of hydroxyl containing compound using a carbonate ester linkage(Jamieson, G. C. et al. U.S. Pat. No. 7,632,519). Carbonate and etherlinkages have also been utilized for a transient phenolic alcoholprotection using photolytically cleavable molecular partners (Katritzky,A. R. et al. J. Org. Chem. 2003, 68, 9100-9104).

The chemical stability of a carbamate is generally considered to besomewhere between an ester and an amide, and they can be substrates forboth esterases and amidases (for a recent review on prodrug approach indrug discovery, see: Rautio, J. et al. Nat. Rev. Drug Discov. 2018, 17,559-587). Examples of simple aliphatic amines conjugated to a capsaicinwith a carbamate linkage, thereby functioning as a protecting group forthe analgesics, exist in the literature. Here, in embodiments, the useof amines with one extra functional group such as a carboxyl or ahydroxyl can be used as a handle for attachment of a second molecule,either inert for additional hydrophobicity or from using a molecule withbiological and pharmacological activity (such as a known drug) forpossible modulation of the overall therapeutic profile. In embodiments,amino containing heterocycles or heteroaryls with varied structuralcomplexity can be used as capsaicin prodrug partners for carbamatelinkage stability modulation and tuning (see, e.g., FIG. 1).

Fatty Acid Assessment of Capsaicin Palmitate

Pharmaceutical compounds may be palmitated. This is a preferredembodiment used to reduce or eliminate capsaicin pungency. Capsaicin isa highly selective agonist for TRPV1. TRPV1 is a ligand-gated,non-selective cation channel preferentially expressed on small-diametersensory neurons, especially C-fibers that specialize in the detection ofpainful or noxious sensations. TRPV1 responds to noxious stimuliincluding capsaicin, heat, and extracellular acidification, and willintegrate simultaneous exposures to these stimuli.

Reduction of the inherent pungency of capsaicin, its analogs and otherTRPV1 agonists through modification of the chemical structure of theparent molecule is disclosed by the present invention. Here, it has beensurprisingly discovered that in order to avoid the burning properties ofcapsaicin on the skin, by design, a pro-drug such as capsaicin palmitatecan be made where a linker or helper molecule such as a fatty acid, canbe released leaving the capsaicin molecule or its structural derivative,that can be independently delivered to the TRPV1-associated neuron,and/or after the molecule has reached its site of action. Therefore, thechemical-release kinetics of a parent drug may impart two importantproperties: (a) reduced and/or delayed pungency and (b) prolonged andslow release for extended duration of pharmacological activity.

The capsaicin, capsaicinoids or other TRPV1 agonist compounds can bechemically modified to control the rate at which capsaicin,capsaicinoid, or other TRPV1 agonist (from here, capsaicin) isbioavailable through enzymatic and/or hydrolytic conversions of sidechains. In the case of CP, an ester or other hydrolyzable linker groupmay be covalently bonded to the phenol position of capsaicin such thatupon administration, enzymes and/or water may induce hydrolysis of thelinkage to liberate the capsaicin molecule where the hydrolyzable groupacts to sterically hinder the pungent moiety of the capsaicin molecule.

Fatty acids and their associated derivatives are the primary componentsof lipids. The length and degree of saturation of the hydrocarbon chainis highly variable between each fatty acid, and dictates the associatedphysical properties (e.g., melting point and fluidity). Moreover, thehydrocarbon chains of fatty acids are responsible for the hydrophobicproperties (insoluble in water) exhibited by lipids. Fatty acids, likecapsaicin, are comprised of hydrocarbon chains (saturated andunsaturated, respectively). However, while fatty acids terminate withcarboxylic acid groups and capsaicin terminates with a4-hydroxy-3-methoxyphenyl ring, these are both hydrophilic structures.These aliphatic structures are similar in some areas and different inothers, thereby rendering the molecules chemically compatible.

The present invention has been described with reference to particularembodiments having various features. In light of the disclosure providedabove, it will be apparent to those skilled in the art that variousmodifications and variations can be made in the practice of the presentinvention without departing from the scope or spirit of the invention.One skilled in the art will recognize that the disclosed features may beused singularly, in any combination, or omitted based on therequirements and specifications of a given application or design. Whenan embodiment refers to “comprising” certain features, it is to beunderstood that the embodiments can alternatively “consist of” or“consist essentially of” any one or more of the features. Any of themethods disclosed herein can be used with any of the compounds and/orcompositions disclosed herein or with any other compounds and/orcompositions. Likewise, any of the disclosed compounds and/orcompositions can be used with any of the methods disclosed herein orwith any other methods. Other embodiments of the invention will beapparent to those skilled in the art from consideration of thespecification and practice of the invention.

It is noted in particular that where a range of values is provided inthis specification, each value between the upper and lower limits ofthat range, to the tenth of the unit disclosed, is also specificallydisclosed. Any smaller range within the ranges disclosed or that can bederived from other endpoints disclosed are also specifically disclosedthemselves. The upper and lower limits of disclosed ranges mayindependently be included or excluded in the range as well. The singularforms “a,” “an,” and “the” include plural referents unless the contextclearly dictates otherwise. It is intended that the specification andexamples be considered as exemplary in nature and that variations thatdo not depart from the essence of the invention fall within the scope ofthe invention. Further, all of the references cited in this disclosureare each individually incorporated by reference herein in theirentireties and as such are intended to provide an efficient way ofsupplementing the enabling disclosure of this invention as well asprovide background detailing the level of ordinary skill in the art.

1. A prodrug, comprising a capsaisinoid joined at a free phenolichydroxyl group to at least one linked moiety via a carbamate-containinglinkage.
 2. The prodrug of claim 1, wherein the at least one linkedmoiety comprises a hydrophobic molecule, a molecule with biologicalactivities, or a molecule with physiological activities.
 3. The prodrugof claim 1, wherein the at least one linked moiety comprises ahydrocarbon, a hetero hydrocarbon, or a heteroaryl moiety.
 4. Theprodrug of claim 1, comprising a compound of formula:

wherein: Cpsn represents the capsaicinoid; X is C or N; R is H or C(O)R′where R′ is a C₁₋₂₀ hydrocarbon; when X is C, m is 0 to 3, and n is 0 to2; and when X is N, m is 2, and n is
 2. 5. The prodrug of claim 1,comprising a compound of formula:

wherein: Cpsn represents the capsaicinoid; X is C or N; m is 0 to 3; nis 0 to 2; when X is C, m is 0 to 3, n is 0, and R is OH, OR′ where R′is a C₁₋₂₀ hydrocarbon, a molecule with analgesic properties, or amolecule with pharmacological properties; when X is N, and n is 0, m is2, and R is a C₁₋₂₀ hydrocarbon, and when X is N, and n is 1 or 2, m is2, and R is OH, OR′ where R′ is a C₁₋₂₀ hydrocarbon, a molecule withanalgesic properties, or a molecule with pharmacological properties. 6.The prodrug of claim 1, comprising a compound of formula:

wherein Cpsn represents the capsaicinoid; X is CH; R is H or C(O)R′where R′ is a C₁₋₂₀ hydrocarbon; m is 1 to 2; and n is 1 to
 2. 7. Theprodrug of claim 1, comprising a compound of formula:

wherein: Cpsn represents the capsaicinoid; X is CH; R is H or C(O)R′where R′ is a C₁₋₂₀ hydrocarbon; and m is 0 to
 2. 8. The prodrug ofclaim 1, comprising a compound of formula:

wherein: Cpsn represents the capsaicinoid; X is CH; R is H, a C₁₋₂₀hydrocarbon, a molecule with analgesic properties, or a molecule withpharmacological properties; and m is 1 to
 2. 9. The prodrug of claim 1,comprising a compound of formula:

wherein: Cpsn represents the capsaicinoid; X is CH; R is H a C₁₋₂₀hydrocarbon, a molecule with analgesic properties, or a molecule withpharmacological properties; and m=1 to
 2. 10. The prodrug of claim 1,comprising a compound of formula:

wherein: Cpsn represents the capsaicinoid; X is sp3 or sp2 hybridizedcarbon (C); m=1 to 2; n=1 to 2; and each Y is F, or both Y togetherrepresent ═O. 11-12. (canceled)
 13. The prodrug of claim 1, comprising:

wherein: Cpsn represents the capsaicinoid; and X, Y, and Z are C, or twoof X, Y, and Z are N and the remaining one of X, Y, and Z is C. 14-20.(canceled)
 21. A prodrug, comprising a compound of formula (I) or (II):

wherein: Cpsn represents a capsaicinoid; R is H, a C₁₋₂₀ hydrocarbon, amolecule with analgesic properties, or a molecule with pharmacologicalproperties; and the unsaturated hydrocarbon moiety comprises two linkingcarbon atoms, or comprises a benzene ring optionally substituted with upto 4 substituents selected from the group consisting of a hydrocarbon, ahalogen, a hydroxyl, an alkoxy, and combinations thereof.
 22. (canceled)23. A prodrug, comprising capsaicin linked to at least one additionalstructure having hydrophobicity greater than capsaicin via at least onelinker.
 24. The prodrug of claim 23, wherein the capsaicin is linked viathe at least one linker to the at least one additional structure byester bond formation with at least one carboxylic diacid.
 25. Theprodrug of claim 23, wherein the capsaicin is linked via by way of theat least one linker to at least one additional structure by ester bondformation with at least one symmetrical carboxylic diacid.
 26. Theprodrug of claim 23, wherein the linker is disposed on a vanilloidring-end of the capsaicin.
 27. The prodrug of claim 23, comprising acompound of formula:CpsnO(O)C—(CH₂)n-CO₂R wherein: Cpsn represents a capsaicinoid; n=0 to20; R=H or a C₁₋₂₀ hydrocarbon, a molecule with analgesic properties, ora molecule with pharmacological properties.
 28. A composition,comprising at least one prodrug of claim 23 and at least one compound,wherein: the prodrug is selected from the group consisting of apalmitated ester of capsaicin, a derivative of capsaicin palmitate, andcombinations thereof; and the at least one compound is selected from thegroup consisting of cannabidiol, an essential oil, a wax, hyaluronicacid, jojoba, curcumin, kinetin, nicotinamide, and combinations thereof.29. The prodrug of claim 1, comprising a compound of formula:

wherein: Cpsn represents the capsaicinoid; n=1 to 2; and m=1 to 2.